Abstract While immunotherapies have achieved remarkable success in cancer care in recent years, a large percentage of patients remain unresponsive to currently available treatments. Growing evidence indicates dysfunctional innate and adaptive immune responses in the tumor microenvironment are responsible for tumor evasion that limits the efficacy of the current immunotherapies. Efficacious cancer immunotherapy requires a holistic, system approach to identify and engage key molecular and cellular pathways as well as tumor microenvironment signals to benefit a broad spectrum of cancer patients. The overarching goal of this U54 i3 Center application is to harness research synergy in immunobiology, protein engineering and cancer nanotechnology to develop and validate new nano-immuno-oncology therapeutics for cancer therapy. Four investigators, Zhijian `James' Chen, Yang-Xin Fu, Baran Sumer, and Jinming Gao, supported by the Administrative Core, will advance the frontier of knowledge of molecular and cellular engineering of the tumor immune milieu for robust antitumor immunity. Each project will bring a unique toolset and therapeutic strategy to tackle the immune refractory challenges in solid tumors. Dr. Chen will lead Project 1 to investigate the role of cGAS-STING pathway in intrinsic tumor immunity and evaluate antitumor efficacy of cGAMP nanoparticles in endogenous tumor models. Dr. Fu will lead Project 2 to engineer tumor-targeted delivery of CD47 and T cell activators (IL-2/IL-15) to stimulate innate and adaptive antitumor immunity in the tumor microenvironment. Dr. Gao and Dr. Sumer will lead Project 3 to establish CD47-encoded ultra-pH sensitive nanoparticles as a broad nanoplatform for tumor-targeted delivery of innate and adaptive immune modulators. If successful, our studies will develop innovative and synergistic combinations of small molecular agonists, engineered antibodies and cytokines, and pH sensitive nanoparticle technology. The U54 i3 Center will create a new paradigm for cancer immunotherapy by targeting key molecular, cellular and tumor microenvironment signals to generate and sustain tumor-specific innate and adaptive immunity. Ultimately, this paradigm could significantly advance clinical care for patients with intractable cancers.